Flavopiridol circumvents Bcl-2 family mediated inhibition of apoptosis anddrug resistance in B-cell chronic lymphocytic leukaemia

Flavopiridol, a synthetic flavone, is currently under clinical investigatio n for the treatment of B-cell chronic lymphocytic leukaemia (B-CLL). In thi s study, we examined the in vitro effects of flavopiridol and fludarabine o n B-CLL cells from 64 patients (36 treated and 28 untreated) in terms of ap optosis induction and Bcl-2 family expression. Both flavopiridol and fludar abine induced apoptosis in all the samples tested with mean LD50 values (+/ - SD) of 59.7 nmol/l (+/- 36.5) and 6.2 mu mol/l (+/- 7.5) respectively. Me an flavopiridol LD50 values were not significantly different between the tr eated and untreated patient groups (P = 0.35), whereas the fludarabine LD50 values were significantly higher in the previously treated patient group ( P = 0.01). Bcl-2 and Mcl-1 expression were downregulated in both flavopirid ol and fludarabine-induced apoptotic cells, but the increase in Bax express ion that accompanied fludarabine-induced apoptosis was not evident in flavo piridol-treated cells. In addition, Bcl-2:Bax ratios were not predictive of flavopiridol cytotoxicity (P = 0.82), whereas they were highly predictive of in vitro responsiveness to fludarabine (P = 0.001). Overall, these findi ngs suggest that flavopiridol exerts its cytotoxic effect through a novel c ell-death pathway that is not subject to the Bcl-2 family mediated resistan ce mechanisms that reduce the efficacy of many conventional chemotherapeuti c drugs.